Outline of Lecture
CHRONIC INFLAMMATION
DEFINITION
Inflammation of prolonged duration
(weeks and months) in which:
- Active inflammation
- Tissue injury
- Attempts at repair
coexist, in a varying combination
CAUSES
- •Persistent infection by certain microorganism (of low toxicity)
- •Prolonged exposure to toxic agents
- exogenous (silicosis)
- endogenous (atherosclerosis)
- Autoimmunity
GENERAL FEATURES
Mononuclear cell infiltration
Tissue destruction and necrosis
Proliferative changes
DIFFERENCES BETWEEN ACUTE AND CHRONIC INFLAMMATION
ACUTE INFLAMMATION
- •Duration= short
- •Onset= acute
- •Inflammatory cells= neutrophils, macrophages
- •Vascular changes= Active vasodilation, increased permeability
- •Fluid exudation and edema= +
- •Tissue necrosis= -, seen in suppurative and necrotizing inflammation
CHRONIC INFLAMMATION
Long (weeks to months)
Insidious
Lymphocytes, plasma cells, macrophages and fibroblasts
Angiogenesis, granulation tissue
SYSTEMIC EFFECTS
Fever
Anemia
Leucocytosis
Raised ESR
Secondary systemic amyloidosis
CELLS INVOLVED IN CHRONIC INFLAMMATION
Mononuclear- phagocyte system
Lymphocytes
Plasma cells
Eosinophils
Mast cells
Neutrophils (in some cases)
MONONUCLEAR-PHAGOCYTE SYSTEM
- •Closely related cells of bone marrow origin-
Blood monocytes (t=1/2 1 day)
Tissue macrophages (t=1/2 several months)
Kupffer cells (liver)
Histiocytes
Alveolar macrophages
Microglia (CNS)
Osteoclast (bone)
Dendritic cells and Langerhans cells (skin)
Macrophages of bone marrow
Tingible body cells of germinal centres (lymph node)
Littoral cells of splenic sinusoids
Mesengial cells of glomerulous
Key macrophage events
Recruitment from circulation
Local proliferation
Immobilization
Differentiation (kupffer cells, microglia, osteoclast)
ROLE OF MACROPHAGES IN INFLAMMATION
Phagocytosis and pinocytosis
Antigen processing and antigen presentation
Constituents of granulomas
Regulate lymphocytes response
Secretion of biologically active substances
PRODUCTS RELEASED BY MACROPHAGES
ENZYMES~
- •Neutral proteases (elastases, collagenases)
- •Acid hydrolases (phosphatases, lipases)
- •Plasma proteins~ Complement components (e.g. C1 to C5, properdin)
- •Coagulation factors (e.g. Factor V, VIII, tissue factor)
- •Reactive metabolites of oxygen
- •Nitric oxide
- •Eicasonoids
- •Cytokines (IL-1, TNF, IL-8)
- •Growth factors (PDGF, EGF, TGF-b, TGF)
LYMPHOCYTES
- •Ab production and humoral immunity (B-cells)
- •Cell mediated immunity (T-cells)
- CD4+ helper T cells
- CD8+ suppressor T cells
- •Regulate macrophage response
PLASMA CELLS
Develop from activated B- lymphocytes
Antibody synthesis and secretion
against persistant antigen or altered tissue components
EOSINOPHILS
Inflammation associated with
Allergic responses
Parasitic infestations
Weakly phagocytic
Effector function by degranulation
Eosinophilic granule protein
Biologically active proteins
Includes
Major basic protein (MBP)
Eosinophilic cationic protein
Eosinophilic derived neurotoxins
Eosinophil peroxidase
MAST CELL
Bear receptor for Fc portion of IgE antibody
Degranulate when crosslinked with antigen
Basophilic granules
- Histamine
- Proteoglycans
- Glycosidases
ROLE OF NEUTROPHILS
Persist in some forms of chronic inflammation
Induced by
- persistent microbes or
- mediators produced by macrophages and T-lymphocytes
Examples: Chronic osteomyletis, Chronic damage in lungs (Smokers)
Outcome of chronic inflammation
Ulcers
Fistulas
Granulomatous diseases
Fibrotic diseases
and combinations of the above
Examples of chronic inflammatory diseases
Tuberculosis
Sarcoidosis
Rheumatoid arthritis and other connective tissue diseases
Inflammatory bowel diseases (Crohns disease, ulcerative colitis)
Silicosis and other pneumoconioses
Peptic ulcer of the duodenum and stomach
Liver cirrhosis
CLASSIFICATION
- •Chronic inflammation
- Chronic non specific inflammation
- Chronic granulomatous inflammation
Chronic granulomatous inflammation:
Characterized by focal accumulation of activated macrophages, which often develop an epithelial like (epitheliod) appearance (granuloma).
Primary granulomatous conditions
Bacterial
Tuberculosis
Leprosy
Syphilis
Granuloma inguinale
Brucellosis
Cat scratch disease
Tularemia
Fungal
Histoplasmosis
Coccidiomycosis
Blastomycosis
Cryptococcosis
Actinomycosis
Parasitic
Schistosomiasis
Trichiniasis
Primary granulomatous condition (CONTD)
Foreign body type
Foreign body granulomatosis
Silicosis
Talc granuloma
Metal induced
Berylliosis
Zerconium
granulomatosis
Miscellaneous
Sarcoidosis
Crohn’s disease
Wegener’s granulomatosis
Giant cell arteritis
Major features
- •Mononuclear cell infiltrate
- Lymphocytes
- Macrophages
- Plasma cells
- •Epitheliod cells
- •Giant cell
- •Necrosis(+/-)
- •Fibrosis
Epitheliod cells
These are activated macrophages with epithelial (squamous) cell like appearance
Cells with indistinct cell boundaries
- Abundant pale staining granular
cytoplasm
- Elongated/oval slipper shaped nuclei
Weakly phagocytic
Giant cells
When macrophages (epitheliod) cells fail to deal with microbes to be removed, they fuse together to form multinucleated giant cells
40-50 µm
Weakly phagocytic
Giant cells
Giant cells in inflammation
Langhan’s giant cells
Foreign body type
Touton giant cell
Aschoff cells
Tumour giant cells
Reed-Sternberg cells
Anaplastic tumour giant cells
Giant cells in giant cell tumour of the bone
Giant cells (Contd)
Miscellaneous-
Warthin finkeldy cells (measles)
Osteoclasts, megakaryocyte, syncytiotrophoblast
Langhans giant cell
GIANT FOREIGN BODY CELL
Granuloma
A microscopic aggregation of activated macrophages transformed into epitheliod cells surrounded by a collar of mononuclear leukocytes
With time, develops an enclosing rim of fibroblasts and connective tissue
Types of granuloma
Foreign body granuloma
Immune granuloma
GRANULOMA
Formation of granuloma
Injury
↓
Failure to digest the agent
↓
Weak inflammatory response
↓
Persistence of injurious agent
↓
T-cell mediated immune response
↓
Activation of T cells, monocyte chemotactic factor(C5a, MCP-1, growth factor PDGF, TGF-β)
↓
Recruitment of circulating monocytes and proliferation of tissue macrophages
↓
accumulation and activation of macrophages
↓
Transformation into epitheliod and giant cells
↓
GRANULOMA
GRANULOMA FORMATION
Tuberculosis
Protype of immune granuloma
Caseating garnulomatous lesion
Mycobacterium tuberculosis (Acid fast bacilli)
Pathogenicity is related to ability to escape killing by macrophages and induce delayed type IV hypersensitivity reaction
Formation of tubercle
Initial neutrophilic response to TB bacilli
↓
Neutrophils destroyed by organism
↓
Proliferation of macrophages (after~12 hrs)
↓
Phagocytosis of TB bacilli by macrophages
↓
Activate CD4 + T lymphocytes
Morphological transformation of activated macrophages
↓
Epitheliod cells
↓
Fuse to form giant cells
↓
Hard tubercle formation
(role of cytokines released in response to sensitized CD4 + T cells and constituents of bacterial cell wall
Interaction of mycobacteria with activated T-cells
– direct action of CD8+ suppressor T cells
-action of CD4+helper T cells (via INF-γ)
Direct toxicity of mycobacteria to macrophages
↓
Development of central caseation necrosis
↓
Soft tubercle
(caseating granuloma of tuberculosis)
Tubercular granuloma
ZN staining
